Serotonin(1A) receptor ligands act on norepinephrine neuron firing throughexcitatory amino acid and GABA(A) receptors: A microiontophoretic study inthe rat locus coeruleus

It was previously shown that the excitatory effect of the 5-HT1A agonist 8- OH-DPAT on firing activity of locus coeruleus (LC) norepinephrine (NE) neur ons and the inhibitory action of the 5-HT1A antagonist WAY 100,635 are depe ndent on the presence of 5-HT neurons, whereas the inhibitory action of the 5-HT2 agonist DOI is not. Using in vivo extracellular unitary recordings p erformed in anesthetized rats, iontophoretic applications of the excitatory amino acid antagonist kynurenate attenuated the enhancement in firing prod uced by glutamate and kainate. In contrast, GABA applications decreased the firing activity of NE neurons which was attenuated by the enhancement prod uced by glutamate and kainate. In contrast, GABA applications decreased the firing activity of NE neurons which was attenuated by the GABA(A) receptor antagonist bicuculline. 8-OH-DPAT (10-60 mug kg(-1), i.v.) produced a dose -dependent enhancement in the firing activity of NE neurons that was abolis hed in the presence of kynurenate application. The selective 5-HT1A recepto r antagonist WAY 100,635 (100 mug kg(-1), i.v.) suppressed NE firing which was reversed by the selective 5-HT2A antagonist MDL 100,907 (200 mug kg(-1) , i.v.). In the presence of bicuculline, the inhibitory effect of WAY 100,6 35 was blunted. These results suggest that WAY 100,635 mainly attenuates NE neuron firing by blocking inhibitory 5-HT1A receptors on glutamatergic neu rons, thereby enhancing glutamate release and activating excitatory amino a cid receptors, possibly of the kainate subtype, on 5-HT terminals. The ensu ing increased 5-HT release would then act on excitatory 5-HT(2)A receptors on GABA neurons that would ultimately mediate the inhibition of NE neurons. The prevention of the excitatory action of 8-OH-DPAT on NE neuron firing b y kynurenate is also consistent with this neurocircuitry. (C) 2001 Wiley-Li ss, Inc.